Phosphodiesterase 4D promotes angiotensin II-induced hypertension in mice via smooth muscle cell contraction

Hypertension is a common chronic disease, which leads to cardiovascular and cerebrovascular diseases, and its prevalence is increasing. Cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway participates in multiple cardiovascular diseases. Phosphodiesterase (PDE) 4 has been shown to regulate PKA activity via cAMP specific hydrolysis. However, whether PDE4-cAMP-PKA pathway influences hypertension remains unknown. Herein, we reveal that PDE4D (one of PDE4 isoforms) expression is upregulated in angiotensin II (Ang II)-induced hypertensive mice aortas. Furthermore, knockout of Pde4d in mouse smooth muscle cells (SMCs) attenuate Ang II-induced high BP, arterial wall media thickening, vascular fibrosis and vasocontraction. Upon further investigation, we find that Pde4d deficiency activate PKA-AMP-activated protein kinase signaling pathway to inhibit myosin phosphatase targeting subunit 1-myosin light chain phosphorylation, relieving Ang II-induced SMC contraction in vitro and in vivo . These results indicate that PDE4D may be a potential target for hypertension therapy.